Summary Focal failure recent of significant hypothesis-driven segmental glomerulosclerosis (FSGS) is a major cause of proteinuria and renal that leads to end stage renal disease (ESRD) in over 50% of the cases. Despite important advances in the understanding of FSGS etiopathogenesis, mechanisms disease initiation and progression are still largely unknown. Limited efficacy and toxicities associated with existing therapies urge for the identification of new, approaches. We reported the novel finding that, in Adriamycin and CD2AP-/- murine models of FSGS, complement regulator decay accelerating factor (DAF) is downregulated on podocyte membranes, which unleashes restraints to complement activation and leads to the formation of C3a. Signaling of C3a/C3aR on podocytes results into cytoskeleton rearrangement. Additional preliminary data indicate that, in humans with FSGS, DAF is downregulated and urinary levels of C3a correlate with proteinuria and C3d deposition in the glomeruli. This supports the hypothesis that, in murine and human FSGS, filtered and/or kidney-produced complement components undergo activation through the alternative pathway initiated by DAF downregulation and promote podocyte injury and glomerulosclerosis through C3a/C3aR activation. We will test this hypothesis by determining the source of urinary complement (systemic versus renal), the pathway of complement activation (alternative, classical, or MBL), and the in vivo effect of C3a/C3aR on podocytes (aim 1). We will also decipher the implicated molecular mechanisms (aim 2). The results of the research project will provide new insight on the role of complement in FSGS pathogenesis regardless of outcome. The data have the potential to explain previously published observations associating complement deposition in the glomeruli of patients with FSGS with renal outcomes. Finally, the results could significantly change clinical practice through providing supporting evidence for the use of complement or complement receptor inhibitors to prevent or retard progression of FSGS and other proteinuric glomerular diseases.